U.S. patent application number 13/265564 was filed with the patent office on 2012-02-09 for liquid formulations of salts of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piperazine.
This patent application is currently assigned to H. LUNDBECK A/S. Invention is credited to Heidi Lopez De Diego, Svend Treppendahl.
Application Number | 20120035188 13/265564 |
Document ID | / |
Family ID | 42669509 |
Filed Date | 2012-02-09 |
United States Patent
Application |
20120035188 |
Kind Code |
A1 |
Treppendahl; Svend ; et
al. |
February 9, 2012 |
LIQUID FORMULATIONS OF SALTS OF
1-[2-(2,4-DIMETHYLPHENYLSULFANYL)PHENYL]-PIPERAZINE
Abstract
Liquid formulations of lactic acid addition salts of
1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine are
provided.
Inventors: |
Treppendahl; Svend; (Virum,
DK) ; Lopez De Diego; Heidi; (Naerum, DK) |
Assignee: |
H. LUNDBECK A/S
Valby
DK
|
Family ID: |
42669509 |
Appl. No.: |
13/265564 |
Filed: |
April 16, 2010 |
PCT Filed: |
April 16, 2010 |
PCT NO: |
PCT/DK2010/050084 |
371 Date: |
November 1, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61214540 |
Apr 24, 2009 |
|
|
|
Current U.S.
Class: |
514/255.03 ;
544/395 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 43/00 20180101; A61P 25/18 20180101; A61P 25/28 20180101; C07C
59/08 20130101; A61P 25/30 20180101; C07D 295/096 20130101; A61K
9/08 20130101; A61P 25/00 20180101; A61P 25/04 20180101; A61P 25/24
20180101; A61K 31/495 20130101 |
Class at
Publication: |
514/255.03 ;
544/395 |
International
Class: |
A61K 31/4965 20060101
A61K031/4965; A61P 25/24 20060101 A61P025/24; C07D 241/04 20060101
C07D241/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 24, 2009 |
DK |
PA200900531 |
Claims
1. A liquid pharmaceutical formulation comprising a salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine selected from
the DL-lactic acid addition salt, L-lactic acid addition salt and
the D-lactic acid addition salt.
2. The liquid formulation according to claim 1, wherein said salt
is the DL-lactic acid addition salt.
3. The liquid formulation according to claim 1, wherein said salt
is the L-lactic acid addition salt.
4. The liquid formulation according to claim 1, wherein said salt
is the D-Lactic acid addition salt.
5. The liquid formulation according to claim 1, wherein the
concentration of said salt is above 2.5 mg/mL.
6. A method for the treatment of a disease selected from mood
disorders; major depressive disorder; general anxiety disorder;
panic disorder; post traumatic stress disorder; depression
associated with cognitive impairment, Alzheimer's disease or
anxiety; depression with residual symptoms; chronic pain; eating
disorder or abuse, said method comprising the administration of a
therapeutically effective amount of a liquid formulation according
to claim 1 to a patient in need thereof.
7. The method according to claim 6, wherein a predetermined volume
of said liquid formulation is measured out and the resulting volume
added to a liquid, which liquid is administered orally to the
patient.
8. (canceled)
9. The method according to claim 6 wherein said salt is the
DL-lactic acid addition salt.
10. The method according to claim 9, wherein said salt is the 0
form of the DL-lactic acid addition salt.
11. The method according to claim 6, wherein said salt is the
L-lactic acid addition salt.
12. The method according to claim 11, wherein said salt is the MH 2
form of the L-lactic acid addition salt.
13. The method according to claim 6, wherein said salt is the
D-Lactic acid addition salt.
14. The method according to claim 6, wherein said liquid
formulation comprises above 2.5 mg/mL of said salts.
15-19. (canceled)
20. A compound which is the L-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
21. The compound according to claim 20 which is the MH 2 form of
the L-lactic acid addition salt.
22. A compound which is the D-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
23. A compound which is the .beta. form of the DL-lactic acid
addition salt.
24. A container fitted with a drop aggregate, which container
comprises a liquid formulation according to claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to liquid pharmaceutical
formulations of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
BACKGROUND OF THE INVENTION
[0002] The compound
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (compound I) has
been disclosed in WO 03/029232 as the free base. Compound I has the
molecular structure depicted below.
##STR00001##
[0003] Different pharmaceutically acceptable acid addition salts of
Compound I has been disclosed in WO 2007/144005, including the
lactic acid addition salt.
[0004] Compound I has been reported to exert serotonin transporter
inhibition (WO 03/029232) and is said to be useful for the
treatment of affective disorders, e.g. depression and anxiety. In
addition, compound I exerts 5-HT.sub.3 antagonism and 5-HT.sub.1A
agonism which suggests this compound to be useful e.g. in the
treatment of cognitive impairment in depressed patients, and the
treatment of pain and residual symptoms in depression (WO
2007/144005 and WO 2008/113359).
[0005] In vitro and in vivo experiments conducted with compound I
describing receptor efficacy and disease pharmacology have been
outlined in WO 03/029232, WO 2007/144005 and WO 2008/113359.
[0006] Compound I has been tested in clinical trials in patients
using HAM-D (Hamilton Rating Scale for Depression) as clinical
end-point; for details see WO 2008/113359. The HAM-D scale may be
used to assess the severity of depression in patients by means of a
24 items questionnaire. According to the outcome of the clinical
study compound I is believed to be particularly useful in the
treatment of depression avoiding sleep and sexual related adverse
events (WO 2008/113359).
[0007] For many pharmaceutical compounds, oral administration of a
tablet, capsule, pill or similar intended for swallowing is the
preferred administration form. However, some patients, e.g. elderly
and paediatric patients may have difficulties swallowing, and
liquid solutions may be a suitable alternative avoiding the need
for swallowing tablets, capsules, pills, etc. A liquid solution
further provides a possibility of a flexible dosing regime. In
order to limit the volume of a liquid solution it is necessary to
have a high concentration of the active ingredient in the solution,
which again requires a high solubility of the active
ingredient.
[0008] The present invention is related to liquid formulations of
compound I.
SUMMARY OF THE INVENTION
[0009] The present inventors have surprisingly found that the
L-lactic acid addition salt (=L-lactate), the D-lactic acid
addition salt (=D-lactate) and the DL-lactic acid addition salt
(=DL-lactate) of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine
are highly soluble. Accordingly, the present invention relates to a
liquid formulation comprising the L-lactic acid addition salt, the
D-lactic acid addition salt and/or the DL-lactic acid addition salt
of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
[0010] In one embodiment, the invention relates to a compound which
is the L-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
[0011] In one embodiment, the invention relates to a compound which
is the D-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
[0012] In one embodiment, the invention relates to a method of
treatment, said method comprising the administration of a liquid
formulation of the present invention to a patient in need
thereof.
[0013] In one embodiment, the invention relates to the use of a
salt of the present invention in the manufacture of a liquid
pharmaceutical composition for the treatment of certain
diseases.
[0014] In one embodiment, the invention relates to a salt of the
present invention for use in the treatment of certain diseases,
wherein said salts is in a liquid formulation.
[0015] In one embodiment, the present invention relates to a
container comprising a liquid formulation of the present invention,
wherein said container is fitted with a drop aggregate.
FIGURES
[0016] FIG. 1: XRPD of L-lactate anhydrate 1 (AH1)
[0017] FIG. 2: XRPD of L-lactate monohydrate 1 (MH1)
[0018] FIG. 3: XRPD of L-lactate monohydrate 2 (MH2)
[0019] FIG. 4: XRPD of DL-lactate alpha form (.alpha.)
[0020] FIG. 5: XRPD of DL-lactate beta form (.beta.)
[0021] FIG. 6: XRPD of DL-lactate monohydrate (MH), with content of
.alpha.-form
[0022] FIG. 7: XRPD of DL-lactate gamma form (.gamma.), with
content of .alpha.-form
DETAILED DESCRIPTION OF THE INVENTION
[0023] The formulations to which the present invention relates are
all pharmaceutical compositions.
[0024] Characterisation of the crystalline base and the previously
known salts of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine
has been described in WO 2008/113359. The aqueous solubilities of
these salts are shown in Table 2. Table 1 shows XRPD reflections,
melting points and solubility data of salts of the present
invention. As evidenced by the data from Table 1 and 2, the
DL-lactic acid addition salt .beta.-form and the L-lactic acid
addition salt MH2 have exceptionally high solubilities.
Consequently, these salt forms would be suitable for application in
liquid formulations comprising
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazin. According to
table 2, also the mesylate salt benefits from extremely high
solubility. However, use of methane sulfonic acid (mesylate) in
combination with alcoholic solvents in the synthesis of
pharmaceutical compositions involves a risk of obtaining alkyl
mesylate impurities which could be genotoxic (Mutat. Res. 581
(2005) 23-34; Eur. J. Pharm. Sci. 28 (2006) 1-6). Lactate salts are
accordingly superior to mesylate salts for application in
pharmaceutical compositions.
[0025] For convenience, the L-lactic acid addition salt, the
D-lactic acid addition salt and the DL-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine are referred to
as salts of the present invention. Both the L-lactic acid addition
salt and the DL-lactic acid addition salt exist in several
polymorphic forms as shown in the examples. Special mention is made
of DL-lactic acid addition salt .beta. form as the salt of the
present invention. For the sake of convenience lactic acid addition
salts are also referred to as lactates or lactate salts.
[0026] The polymorphic forms are characterized by their respective
XRPD reflections listed in Table 1 and depicted in FIGS. 1-7.
[0027] In the present context the AH1 form of the L-lactate salt is
intended to indicate a anhydrate form characterized by XRPD
reflections at 4.65, 10.96 and 13.97 (.degree.2.theta.), and
further characterized by FIG. 1.
[0028] In the present context the MH1 form of the L-lactate salt is
intended to indicate a first monohydrate form characterized by XRPD
reflections at 4.36, 8.73, 11.18, 11.81, 12.78 and 13.11
(.degree.2.theta.), and further characterized by FIG. 2.
[0029] In the present context the MH2 form of the L-lactate salt is
intended to indicate a second monohydrate form characterized by
XRPD reflections at 5.33, 9.75, 10.10, 14.44 and 14.63
(.degree.2.theta.), and further characterized by FIG. 3.
[0030] In the present context the .alpha. form of the DL-lactate
salt is intended to indicate a first polymorph characterized by
XRPD reflections at 6.67, 8.33, 9.44, 11.82 and 15.35
(.degree.2.theta.), and further characterized by FIG. 4.
[0031] In the present context the .beta. form of the DL-lactate
salt is intended to indicate a second polymorph characterized by
XRPD reflections at 6.01, 10.10, 10.32, 12.06, 12.84, 13.08 and
13.58 (.degree.2.theta.), and further characterized by FIG. 5.
[0032] In the present context the MH form of the DL-lactate salt is
intended to indicate a monohydrate form characterized by XRPD
reflections at 4.37, 8.73, 11.14, 11.78, 12.75 and 13.11
(.degree.2.theta.), and further characterized by FIG. 6.
[0033] In the present context the .gamma. form of the DL-lactate
salt is intended to indicate a third polymorph characterized by
XRPD reflections 4.63, 10.94, 11.65 and 13.93 (.degree.2.theta.),
and further characterized by FIG. 7.
[0034] Lactic acid is also known as 2-hydroxypropionic acid, and it
forms an 1:1 acid addition salt with
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine which is used in
the present invention.
[0035] 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine may be
prepared as disclosed in WO 03/029232 and WO 2007/144005. The
examples disclose specific routes for obtaining the salts of the
present invention. In brief, the L-lactate AH1 and the DL-lactate
.alpha. form may be prepared by addition of L-lactic acid or
DL-lactic acid, respectively, to
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine or vice versa in
a suitable anhydrous organic solvent, such as ethyl acetate,
followed by precipitation, which precipitation may be brought about
by e.g. cooling, removal of solvent, addition of another anhydrous
solvent or a combination thereof.
[0036] The L-lactate MH1 is formed directly by exposure of
L-lactate AH1 to higher relative humidity. The L-lactate MH2 is the
more stable form of the L-lactate monohydrates and is formed by
adding 1 mL of water to 100 mg of the L-lactate MH1. The aqueous
solubility of the L-lactate MH2 is 26 mg/mL. The DL-lactate .beta.
form is obtained from a slurry of the DL-lactate .alpha. form in
water. The .beta. form is the more stable polymorphic modification
of the DL-lactate and has a solubility of 8 mg/mL. The DL-lactate
MH is obtained by exposure of the DL-lactate .alpha. form to high
relative humidity. By heating the DL-lactate MH1 the DL-lactate
.gamma. form has been obtained. Throughout this document (unless
otherwise indicated) an indication of a concentration of a salt of
the present invention, e.g. 5 mg/ml, is intended to indicate a
concentration equivalent the indicated amount of free base, e.g. 5
mg/ml.
[0037] The inventors have noted that the presence of lactic acid in
formulations of the present invention increases the solubility of
salts of the present invention. The presence of lactic acid, either
as D-, L- or DL-lactic acid, may increase the solubility of salts
of the present invention to 20-25 mg/mL.
[0038] Only salts of L-lactic acid and DL-lactic acid have been
made; however 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine is
not chiral, and the L-lactate and the D-lactate are enantiomers,
and therefore the D-lactate exists (as mirror image) in the same
crystal forms and have the same XRPD-patterns, melting points and
solubility as the L-lactate. X-ray powder difractograms (XRPD) for
different forms of L-lactate salt and DL-lactate salt are depicted
in FIG. 1-7.
[0039] Liquid formulations may be intended for oral or parenteral
administration. Liquid formulations for parenteral administration
including infusion solutions are in many aspects similar to other
liquid formulations, but are additionally characterised by being
sterile and isotonic.
[0040] The liquid oral formulation of the present invention may be
presented as a syrup, an elixir, an oral solution, a suspension, or
as a concentrated oral formulation. One advantage of these
administration forms is that the patient does not have to swallow a
solid form, which may be difficult, in particular for elderly and
paediatric patients or for patients with traumas in the mouth or
throat.
[0041] Syrups and elixirs are typically sweetened, flavoured
liquids containing an active pharmaceutical ingredient. Syrups
typically have higher sugar content, and elixirs often contain
alcohol as well. An oral solution is a solution of the active
ingredient. A suspension is a two-phase system comprising solid
particles dispersed in a liquid. Administration of syrups, elixirs,
oral solutions and suspensions typically involves the intake of
relatively large amounts of liquid, i.e. 10-50 mL.
[0042] In contrast hereto, the concentrated oral formulations of
the present invention are administered to the patient by measuring
out a pre-determined volume of said formulation from a suitable
dispenser, adding the resulting volume to a glass of liquid (water,
juice or similar) upon which the patient drinks the liquid. For
convenience, the volume measured out is small, e.g. less than 2 mL,
such as less than 1 mL, such as less than 0.5 mL. As an example of
such product the regulatory authority in the UK, Medicines and
Healthcare Products Regulatory Agency (MHRA), has approved a
concentrated oral formulation comprising the antidepressant
citalopram at 40 mg/ml.
[0043] In a particular embodiment, a concentrated oral formulation
of the present invention is administered to the patient by
measuring out a pre-determined number of drops of said formulation
from a suitable dispenser, e.g. a container with a drop aggregate,
adding the drops to a glass of liquid (water, juice or similar)
upon which the patient drinks the liquid. In this context, a drop
aggregate is an aggregate fitted to a container that effects that a
liquid inside said container may be dispensed from said container
in discrete drops.
[0044] Preliminary results have indicated that the concentrated
oral formulations of the present invention are prone to being
unstable when exposed to light. To overcome this potential problem
the formulation can be stored protected from light e.g. in an
opaque container or in a container that is light protected by a
box.
[0045] The concentration of a salt of the present invention in
concentrated oral formulations is determined by the number of drops
(or the volume) it is desired to collect and the amount of the
salts it is desired to administer. It is generally held that
measuring out around 5-20 drops is an optimal compromise between
safety/efficacy of the treatment on the one hand and convenience on
the other. If the concentration of the salts of the present
invention is too high, i.e. if only a low number of drops is to be
measured out, it may jeopardize safety or efficacy of the
treatment. With a low number of drops, one or two drops more or
less than desired will significantly increase the uncertainty in
the dose provided. On the other hand, if the concentration of the
salts of the present invention is too low, the number of drops to
be measured out is high, which is inconvenient for the patient or
the caretaker.
[0046] With daily dosages of 2.5 mg, a concentrated oral
formulation with a concentration of 2.5 mg of active ingredient per
mL could be appropriate. A concentration of 2.5 mg per mL and a
drop number of 20 drops/mL would make it possible to administer 20
drops for a dose of 2.5 mg.
[0047] With daily dosages of 2.5 mg, a concentrated oral
formulation with a concentration of 5 mg of active ingredient per
mL could be appropriate. A concentration of 5 mg per mL and a drop
number of 20 drops/mL would make it possible to administer 10 drops
for a dose of 2.5 mg.
[0048] With daily dosages of 2.5 mg, a concentrated oral
formulation with a concentration of 10 mg of active ingredient per
mL could be appropriate. A concentration of 10 mg per mL and a drop
number of 20 drops/mL would make it possible to administer 5 drops
for a dose of 2.5 mg.
[0049] With daily dosages of 5 mg, a concentrated oral formulation
with a concentration of 5 mg of active ingredient per mL could be
appropriate. A concentration of 5 mg per mL and a drop number of 20
drops/mL would make it possible to administer 20 drops for a dose
of 5 mg.
[0050] With daily dosages of 5 mg, a concentrated oral formulation
with a concentration of 10 mg of active ingredient per mL could be
appropriate. A concentration of 10 mg per mL and a drop number of
20 drops/mL would make it possible to administer 10 drops for a
dose of 5 mg.
[0051] With daily dosages of 5 mg, a concentrated oral formulation
with a concentration of 20 mg of active ingredient per mL could be
appropriate. A concentration of 20 mg per mL and a drop number of
20 drops/mL would make it possible to administer 5 drops for a dose
of 5 mg.
[0052] With daily dosages of 10 mg, a concentrated oral formulation
with a concentration of 10 mg of active ingredient per mL could be
appropriate. A concentration of 10 mg per mL and a drop number of
20 drops/mL would make it possible to administer 20 drops for a
dose of 10 mg.
[0053] With daily dosages of 10 mg, a concentrated oral formulation
with a concentration of 20 mg of active ingredient per mL could be
appropriate. A concentration of 20 mg per mL and a drop number of
20 drops/mL would make it possible to administer 10 drops for a
dose of 10 mg.
[0054] With daily dosages of 20 mg, a concentrated oral formulation
with a concentration of 20 mg of active ingredient per mL could be
appropriate. A concentration of 20 mg per mL and a drop number of
20 drops/mL would make it possible to administer 20 drops for a
dose of 20 mg.
[0055] Accordingly, in one embodiment a concentrated oral
formulations of the present invention comprise approximately 2.5-20
mg/mL of a salt of the present invention. Particular examples
include approximately 5-20 mg/mL, approximately 5-15 mg/mL,
approximately 5-10 mg/mL, and approximately 2.5, 5, 7.5, 10, 15 or
20 mg/mL.
[0056] In one embodiment, a concentrated oral formulation of the
present invention comprises at least 2.5 mg/mL of a salt of the
present invention.
[0057] In one embodiment, a concentrated oral formulation of the
present invention comprises at least 5 mg/mL of a salt of the
present invention.
[0058] In one embodiment, a concentrated oral formulation of the
present comprises at least 10 mg/mL of a salt of the present
invention.
[0059] In one embodiment, a concentrated oral formulation of the
present comprises at least 20 mg/mL of a salt of the present
invention.
[0060] In addition to a salt of the present application, the oral
formulation of the present application, and in particular the
concentrated oral formulations may comprise solvents, buffers,
surfactants, surface tension modifiers, viscosity modifiers,
preservatives, antioxidants, colorants, taste maskers, flavours
etc.
[0061] Examples of solvents include water and other solvents, which
are miscible with water or solubilizing agents and suitable for
oral purposes. Examples of suitable solvents are ethanol, propylene
glycol, glycerol, polyethylene glycols, poloxamers, sorbitol and
benzyl alcohol. The aqueous solubility of the active ingredient may
further be enhanced by the addition to the solution of a
pharmaceutically acceptable co-solvent, a cyclodextrin or a
derivative thereof.
[0062] A buffer system may be used to maintain the pH of the
formulation in an optimal pH-range. A buffer system is a mixture of
appropriate amounts of a weak acid such as acetic, phosphoric,
succinic, tartaric, lactic or citric acid and its conjugate base.
Ideally, the buffer system has sufficient capacity to remain in the
intended pH range upon dilution with a neutral, a slightly acidic
or a slightly basic beverage.
[0063] Surfactants are substances, which solubilize active
compounds, which are insufficiently soluble in an aqueous medium,
usually with the formation of micelles. Preferably, the surfactant
used should be non-ionic due to less toxicity. High concentrations
of surfactants may be used to allow for dilution during
administration without precipitation. Examples of surfactants
include tweens, spans and mono- and diglycerides.
[0064] Surface tension modifiers may be included to adjust the drop
number for the concentrated oral formulations. An example of a
surface tension modifier is ethanol, which decreases the surface
tension and increases the drop number.
[0065] Viscosity modifiers may be included to adjust the drop
velocity for a concentrated oral formulation. The drop velocity for
a formulation to be measured out in discrete drops from a container
fitted with a drop aggregate should preferably not exceed 2 drops
per second. Examples of viscosity modifiers include ethanol,
hydroxyethylcellulose, carboxymethylcellulose sodium,
methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,
polyethylene glycol and glycerine.
[0066] Preservative agents may be added to prevent the growth of
micro organisms such as bacteria, yeasts and fungi in liquid
formulations, which are likely to be used repeatedly. Suitable
preservatives should be pharmaceutically acceptable,
physicochemical stable and effective in the desired pH range.
Examples of preservative agents include ethanol, benzoic acid,
sorbic acid, methylparaben, propylparaben and benzyl alcohol.
[0067] A drug substance is typically more sensitive to chemical
degradation in dissolved than in solid form; hence it may be
necessary to include an antioxidant in the liquid formulation.
Examples of antioxidants include propyl gallate, ascorbyl
palmitate, ascorbic acid, sodium sulphite, citric acid and
EDTA.
[0068] Colouring agents may be used in some formulations to
introduce a uniformity of appearance to the product. Some active
ingredients may further be very sensitive to light and it may prove
necessary to add colouring agents to the drop formulations to
protect them from light and for the purpose of stabilization.
Suitable colouring agents include for example tartrazine and sunset
yellow.
[0069] Sweetening agents may mask unpleasant taste associated with
some formulations or to achieve a desired taste. Examples of
sweetening agents are saccharin, sodium salt of saccharin, glucose,
sorbitol, glycerol, acesulfame potassium and neohesperidin
dihydrochalcon. The taste may be optimized further by the addition
of one or more flavouring substances. Suitable flavouring
substances are fruit flavours such as cherry, raspberry, black
currant, lemon or strawberry flavour or other flavours such as
liquorish, anis, peppermint, caramel etc. Particular examples of
concentrated oral formulations of lactic acid addition salts of
Compound I, which may be administered with a drop aggregate, are
listed below. Further examples are provided in the Examples
section. By active compound is meant the DL-lactate, the L-lactate
or the D-lactate salt of compound I. 1% of the free base form of
compound I corresponds to 1.3% of the active compound. 2% of the
free base form of compound I corresponds to 2.6% of the active
compound. The examples are merely intended to illustrate the
invention and should not be construed as limiting
[0070] 0.33% active compound
[0071] 0.08% methylparahydroxybenzoate
[0072] 0.02% propylparahydroxybenzoate
[0073] 0.2% hydroxyethylcellulose
[0074] Water q.s. ad 100%
[0075] 0.65% active compound
[0076] 5% hydroxy propyl betacyclodextrin
[0077] 0.02% propyl gallate
[0078] 0.2% sorbinsyre
[0079] Water q.s. ad 100%
[0080] 1.3% active compound
[0081] 0.1% hydroxyethylcellulose
[0082] Water q.s. ad 100%
[0083] 2.6% active compound
[0084] 10% hydroxyl propyl betacyclodextrin
[0085] Water q.s. ad 100%
[0086] The pharmacological profile of compound I is disclosed in WO
03/029232, WO 2007/144005 and WO 2008/113359. In brief, compound I
is an inhibitor of the serotonin transporter, an antagonist at the
5-HT.sub.3 receptor and an agonist at the 5-HT.sub.1A receptor.
Compound I gives rise to an increase in the extracellular levels of
serotonin, noradrenaline, dopamine and acetylcholine in rat brains
[Moore et al, Eur. Neuropsychopharmacol., 18, suppl 4, s321, 2008].
The '359 application also discloses the results from clinical
trials in depressed patients with the corresponding HBr addition
salt which show a surprisingly low level of sleep and sexually
related adverse events.
[0087] On this background, salts of the present invention are
expected to be useful in the treatment of mood disorders, such as
major depressive disorder, generalised anxiety disorder, panic
disorder, post traumatic stress disorder, and depression associated
with anxiety, i.e. co-existing depression and anxiety. The impact
on extracellular acetylcholine levels is expected to translate into
an effect on cognition, cf. the use of acetylcholine esterase
inhibitors in the treatment of Alzheimer's disease. Thus, the salts
of the present invention may also be used in the treatment of
depression associated with cognitive impairment and Alzheimer's
disease.
[0088] A fraction of patients with major depressive disorder will
respond to treatment with e.g. a selective serotonin transport
inhibitor in the sense that they will improve on clinically
relevant scales, such as HAMD or MADRS, but where other symptoms,
such as cognitive and/or sleep symptoms remain. In the present
context, these patients are referred to as suffering form
depression with residual symptoms. The salts of the present
invention are expected to be useful in the treatment of such
patients.
[0089] Pre-clinical data presented e.g. in WO 2008/113359 supports
the notion that compound I may be used in the treatment of pain. In
one embodiment, pain is or pain is associated with chronic pain
including phantom limb pain, neuropathic pain, diabetic neuropathy,
post-herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV
neuropathy, complex regional pain syndrome (CPRS), trigeminus
neuralgia, tic douloureux, surgical intervention (e.g.
post-operative analgesics), diabetic vasculopathy, capillary
resistance, diabetic symptoms associated with insulitis, pain
associated with menstruation, pain associated with cancer, dental
pain, headache, migraine, tension-type headache, trigeminal
neuralgia, temporomandibular joint syndrome, myofascial pain,
muscular injury, fibromyalgia syndrome, bone and joint pain
(osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and
edema resulting from trauma associated with burns, strains or
fracture bone pain due to osteoarthritis, osteoporosis, bone
metastases or unknown reasons, gout, fibrositis, myofascial pain,
thoracic outlet syndromes, upper back pain or lower back pain
(wherein the back pain results from systematic, regional, or
primary spine disease (radiculopathy), pelvic pain, cardiac chest
pain, non-cardiac chest pain, spinal cord injury (SCI)-associated
pain, central post-stroke pain, cancer neuropathy, AIDS pain,
sickle cell pain or geriatric pain. In one embodiment, pain is
irritable bowl syndrome (IBS).
[0090] On the basis of the pharmacological profile, it is also
expected that the salts of the present invention may be useful in
the treatment of eating disorders, such as obesity, binge eating,
anorexia and bulimia nervosa, and substance abuse, such as alcohol,
nicotine and drug abuse.
[0091] Hence, in one embodiment, the invention relates to a method
of treating a disease selected from mood disorders; major
depressive disorder; general anxiety disorder; panic disorder; post
traumatic stress disorder; depression associated with cognitive
impairments, Alzheimer's disease or anxiety; depression with
residual symptoms; chronic pain; eating disorder or abuse said
method comprising the administration of a therapeutically effective
amount of a liquid formulation of the present invention to a
patient in need thereof.
[0092] Due to the very low level of adverse events observed in
treatment with 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine,
a liquid formulation of the present invention may also be useful as
second line treatment for patients who cannot use other drugs, such
as other anti-depressants, such as selective serotonin reuptake
inhibitors (SSRI), selective noradrenalin reuptake inhibitors
(NRI), noradrenaline/serotonin reuptake inhibitors (SNRI) or
tri-cyclics (TCA) due to sleep or sexually related adverse events.
In this embodiment, the patient to be treated has received another
medication (or is still receiving it), which medication was ceased
or reduced (or has to be ceased or reduced) due to sleep or
sexually related adverse events. In one embodiment, said liquid
formulation is a concentrated oral formulation.
[0093] In one embodiment, the patient to be treated has been
diagnosed with the disease said patient is being treated for.
[0094] A typical oral dosage is in the range of from about 0.01 to
about 5 mg/kg body weight per day, preferably from about 0.01 to
about 1 mg/kg body weight per day, administered in one or more
dosages such as 1 to 3 dosages. The exact dosage will depend upon
the frequency and mode of administration, the sex, age, weight and
general condition of the subject treated, the nature and severity
of the condition treated and any concomitant diseases to be treated
and other factors evident to those skilled in the art.
[0095] A typical oral dosage for adults is in the range of 0.5-50
mg/day of a salt of the present invention, such as 1-10 mg/day.
This may typically be achieved by the administration of 0.5-50 mg,
such as 0.5, 1, 2.5, 5, 10, 15, 20 25, 30 or 40 mg of a salt of the
present invention once or twice daily. In case of paediatric
treatment, the dose may be reduced according to age and/or body
weight.
[0096] A "therapeutically effective amount" of a compound as used
herein means an amount sufficient to cure, alleviate or partially
arrest the clinical manifestations of a given disease and its
complications in a therapeutic intervention comprising the
administration of said compound. An amount adequate to accomplish
this is defined as "therapeutically effective amount". The term
also includes amounts sufficient to cure, alleviate or partially
arrest the clinical manifestations of a given disease and its
complications in a treatment comprising the administration of said
compound. Effective amounts for each purpose will depend on the
severity of the disease or injury as well as the weight and general
state of the subject. It will be understood that determining an
appropriate dosage may be achieved using routine experimentation,
by constructing a matrix of values and testing different points in
the matrix, which is all within the ordinary skills of a trained
physician.
[0097] The term "treatment" and "treating" as used herein means the
management and care of a patient for the purpose of combating a
condition, such as a disease or a disorder. The term is intended to
include the full spectrum of treatments for a given condition from
which the patient is suffering, such as administration of the
active compound to alleviate the symptoms or complications, to
delay the progression of the disease, disorder or condition, to
alleviate or relief the symptoms and complications, and/or to cure
or eliminate the disease, disorder or condition as well as to
prevent the condition, wherein prevention is to be understood as
the management and care of a patient for the purpose of combating
the disease, condition, or disorder and includes the administration
of the active compounds to prevent the onset of the symptoms or
complications. Nonetheless, prophylactic (preventive) and
therapeutic (curative) treatment are two separate aspect of the
invention. The patient to be treated is preferably a mammal, in
particular a human being.
[0098] In one embodiment, the invention relates to the use of a
salt of the present invention for the manufacture of a liquid
formulation for the treatment of a disease selected from mood
disorders; major depressive disorder; general anxiety disorder;
panic disorder; post traumatic stress disorder; depression
associated with cognitive deficits, Alzheimer's disease or anxiety;
depression with residual symptoms; chronic pain; eating disorder or
abuse.
[0099] In one embodiment, said salt is chosen from the .beta. form
of the DL-lactate salt and the MH2 form of the L-lactate salt.
[0100] In one embodiment, said liquid formulation is a concentrated
oral formulation.
[0101] In one embodiment, the present invention relates to a salt
of the present invention for use in the treatment of a disease
selected from mood disorders; major depressive disorder; general
anxiety disorder; panic disorder; post traumatic stress disorder;
depression associated with cognitive deficits, Alzheimer's disease
or anxiety; depression with residual symptoms; chronic pain; eating
disorder or abuse, wherein said salt is in a liquid
formulation.
[0102] In one embodiment, said salt is chosen from the DL-lactate
salt and the L-lactate salt.
[0103] In one embodiment, said liquid formulation is a concentrated
oral formulation.
[0104] In one embodiment the present invention relates to a liquid
formulation comprising a salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine selected from
the DL-lactic acid addition salt, the L-lactic acid addition salt
and/or the D-lactic acid addition salt. In particular, said liquid
formulation is a concentrated oral formulation.
[0105] In one embodiment the present invention relates to a
compound which is the L-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. Particular
mention is made of the MH2 form.
[0106] In one embodiment the present invention relates to a
compound which is the L-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine with XRPD
reflections at approximately 5.33, 9.75, 10.10, 14.44 and 14.63
(.degree.2.theta.) e.g. with an XRPD pattern as depicted in FIG.
3.
[0107] In one embodiment the present invention relates to a
compound which is the D-lactic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
[0108] In one embodiment the present invention relates to a
compound which is the .beta. form of the DL-lactic acid addition
salt with XRPD reflections at approximately 6.01, 10.10, 10.32,
12.06, 12.84, 13.08, 13.58 (.degree.2.theta.), e.g. with a XRPD
pattern as depicted in FIG. 5.
[0109] The salts of the present invention may be administered
either alone or in combination with another therapeutically active
compound, wherein the two compounds may be administered either
simultaneously or sequentially. Examples of therapeutically active
compounds which may advantageously be combined with salts of the
present invention include sedatives or hypnotics, such as
benzodiazepines; anticonvulsants, such as lamotrigine, valproic
acid, topiramate, gabapentin, carbamazepine; mood stabilizers such
as lithium; dopaminergic drugs, such as dopamine agonists and
L-Dopa; drugs to treat ADHD, such as atomoxetine; psychostimulants,
such as modafinil, ketamine, methylphenidate and amphetamine; other
antidepressants, such as mirtazapine, mianserin and buproprion;
hormones, such as T3, estrogen, DHEA and testosterone; atypical
antipsychotics, such as olanzapine and aripiprazole; typical
antipsychotics, such as haloperidol; drugs to treat Alzheimer's
diseases, such as cholinesterase inhibitors and memantine, folate;
S-Adenosyl-Methionine; immunmodulators, such as interferons;
opiates, such as buprenorphins; angiotensin II receptor 1
antagonists (AT1 antagonists); ACE inhibitors; statins; and alpha1
adrenergic antagonist, such as prazosin.
[0110] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference in
their entirety and to the same extent as if each reference were
individually and specifically indicated to be incorporated by
reference and were set forth in its entirety herein (to the maximum
extent permitted by law), regardless of any separately provided
incorporation of particular documents made elsewhere herein.
[0111] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention are to be
construed to cover both the singular and the plural, unless
otherwise indicated herein or clearly contradicted by context. For
example, the phrase "the compound" is to be understood as referring
to various "compounds" of the invention or particular described
aspect, unless otherwise indicated.
[0112] Unless otherwise indicated, all exact values provided herein
are representative of corresponding approximate values (e.g., all
exact exemplary values provided with respect to a particular factor
or measurement can be considered to also provide a corresponding
approximate measurement, modified by "about," where
appropriate).
[0113] The description herein of any aspect or aspect of the
invention using terms such as "comprising", "having," "including,"
or "containing" with reference to an element or elements is
intended to provide support for a similar aspect or aspect of the
invention that "consists of", "consists essentially of", or
"substantially comprises" that particular element or elements,
unless otherwise stated or clearly contradicted by context (e.g., a
composition described herein as comprising a particular element
should be understood as also describing a composition consisting of
that element, unless otherwise stated or clearly contradicted by
context).
EXAMPLES
Analysis
[0114] X-Ray powder diffractograms (XRPD) were measured on a
PANalytical X'Pert PRO X-Ray Diffractometer using CuK.sub..alpha.1
radiation. The samples were measured in reflection mode in the
2.theta.-range 5-40.degree. C. using an X'celerator detector.
Throughout this document, diffraction data are indicated .+-.0.1
(.degree.2.theta.).
Example 1
AH1 form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
L-lactate
[0115] 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine base
(5.00 g) was dissolved in ethyl acetate (50 mL) at 50.degree. C.
The solution was a little turbid and was filtered through a paper
filter. L-(+)-lactic acid (1.84 g) was added to the solution and
stirred at room temperature. Precipitation started and the
suspension was stirred at room temperature for two hours and the
product was isolated by filtration. The solid was dried in the
vacuum oven at 40.degree. C. over night. It was not possible to
measure the aqueous solubility of the AH1 as the substance
transforms into monohydrate when exposed to water.
Example 2
MH1 form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
L-lactate
[0116] 100 mg of AH1 form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, L-lactate
from example 1 was left in an open container at ambient conditions
(22.degree. C., 30% RH). It was not possible to measure solubility
of the MH1, as the compound transforms into the MH2 in aqueous
slurry.
Example 3
MH2 form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
L-lactate
[0117] To 100 mg of MH1 form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, L-lactate
from example 2 was added 1 mL of water, and the mixture was left
overnight. The precipitate (MH2-form) is filtered of.
Example 4
.alpha. form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
DL-lactate
[0118] 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine base
(5.00 g) was dissolved in ethyl acetate (50 mL) at 50.degree. C.
The solution was a little turbid and was filtered through a paper
filter and became clear. DL-lactic acid (1.68 g) was added to the
solution and stirred at room temperature. Precipitation started
after two hours. The suspension was stirred at room temperature for
two hours and the product isolated by filtration. The solid was
dried in the vacuum oven at 40.degree. C. over night. It was not
possible to measure the solubility of the .alpha. form in water, as
the compound transformed into the .beta. form in the aqueous
slurry.
Example 5
.beta. form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
DL-lactate
[0119] 100 mg of .alpha. form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-lactate
from example 5 was added 1 mL of water, and the mixture is left
overnight. The precipitate (.beta.-form) was filtered of.
Example 6
MH form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
DL-lactate
[0120] 10 mg of .alpha. form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-lactate
from example 5 was exposed to high relative humidity (25.degree.
C., 95% RH) for 4 h. It was not possible to measure solubility of
MH in water because it transformed into the beta form in aqueous
slurry.
Example 7
.gamma. form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
DL-lactate
[0121] 10 mg of MH form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-lactate
from example 7 was heated to 50.degree. C. It was not possible to
measure aqueous solubility of the .gamma. form because it
transforms into the beta form in aqueous slurry.
Example 8
.beta. form of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,
DL-lactate
[0122] 200 g of
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, HBr (526
mmol) was stirred in Me-THF (3.5 L) and 1 M NaOH (1 L) were added.
The suspension was stirred for 15 minutes after which all solids
were dissolved. The phases were separated, and after blank
filtration the Me-THF phase was reduced to half volume. After
cooling to room temperature DL-lactic acid (1.5 eq .about.789 mmol)
was added and the solution was seeded with 0.5% of the .beta. form.
After 5 minutes, the precipitation starts and the suspension was
left stirring at ambient temperature overnight. The suspension was
then cooled on ice, filtered and washed with 200 mL Me-THF and
dried overnight under vacuum at 50.degree. C.
TABLE-US-00001 TABLE 1 Summary of selected reflection for the XRPD
patterns, melting point and room temperature solubility of the
forms of 1-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl] piperazine,
lactate Melting Crystal Selected XRPD point Solubility Salt Form
reflections (.degree.2.theta.) (.degree. C.) (mg base/mL) L-lactate
AH1 4.65, 10.96, 13.97 ~140 na L-lactate MH1 4.36, 8.73, 11.18, na
na (>26) 11.81, 12.78, 13.11 L-lactate MH2 5.33, 9.75, 10.10, na
26 (pH = 5.2) 14.44, 14.63 DL-lactate .alpha. 6.67, 8.33, 9.44,
11.82, ~119 na 15.35 DL-lactate .beta. 6.01, 10.10, 10.32, ~149 8
(pH = 6) 12.06, 12.84, 13.08, 13.58 DL-lactate MH 4.37, 8.73,
11.14, na na 11.78, 12.75, 13.11 DL-lactate .gamma. 4.63, 10.94,
11.65, ~123 na 13.93 na = non applicable
TABLE-US-00002 TABLE 2 Room temperature solubility of previously
known salt forms of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]
piperazine Solubility Salt (mg base/mL) Crystalline base 0.1 HBr,
.alpha.-form 2.0 HBr, .beta.-form 1.2 HCl 3.0 HCl, MH 2.0 Fumarate
0.4 Maleate ~1 Meso-tartrate ~0.7 L-(+)-tartrate ~0.4
D-(-)-tartrate ~0.4 Sulphate ~0.1 Phosphate ~1 Nitrate ~0.8
Mesylate >45
Example 9
Synthesis of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine
D,L-lactate salt
##STR00002##
[0124] 50 g (132 mmol) of the HBr salt was suspended in 800 mL
toluene and 250 mL (250 mmol; 1.9 eq) 1M aq. NaOH was added. The
two-phase mixture was warmed to 65.degree. C. until all solid has
gone into solution and then cooled to room temperature. The phases
were separated, and the organic phase was evaporated in vacuo to
give a slightly yellow solid. 125 mL ethanol and 20 mL (269 mmol;
2.0 eq) DL-lactic acid (90%) were added, and the suspension was
warmed until all solids were dissolved, followed by cooling to room
temperature. The solution was seeded with a few crystals of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine D,L-lactate
.beta. form, and the suspension was stirred over night at room
temperature and subsequently cooled with an ice-bath. The
precipitate was filtered-off and washed with ethanol, dried in
vacuum oven to give 36.5 g
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine D,L-lactate
.beta. form (71% yield).
Example 10
Concentrated Oral Formulations
[0125] The concentrated oral formulations indicated below were
prepared and exposed to stability testing under conditions as
indicated. 25/60 indicates 25.degree. C. and 60% RH, 40/75
indicates 40.degree. C. and 75% RH, and 60 indicates 60.degree. C.
The numbers indicate the amount of residual active compound
following the test period.
[0126] The residual amount of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine in the oral drop
formulations was determined by gradient reverse-phase HPLC. The
mobile phase consisted of a mixture of water and acetonitrile with
TFA added. Detection was by UV at 226 nm.
a) 1.3% active compound.about.1% free base 0.08%
methylparahydroxybenzoate 0.02% propylparahydroxybenzoate
Water q.s. ad 100%
TABLE-US-00003 [0127] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 10.6 10.6 10.6 1/2 10.6 10.4 10.4 1 10.4 10.5 10.4 2 10.1
10.1 10.2 3 9.8 9.8 9.9
b) 1.3% active compound.about.1% free base 5% hydroxy propyl
betacyclodextrin
Water q.s. ad 100%
TABLE-US-00004 [0128] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 10.4 10.4 10.4 1/2 10.3 10.3 10.3 1 10.4 10.4 10.4 2 9.9
10.1 10.2 3 9.7 9.5 9.8
c) 1.3% active compound.about.1% free base 0.1%
hydroxyethylcellulose
Water q.s. ad 100%
TABLE-US-00005 [0129] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 10.4 10.4 10.4 1/2 10.5 10.6 10.5 1 10.4 10.5 10.5 2 10.1
10.2 10.1 3 9.6 9.5 9.6
d) 1.3% active compound.about.1% free base 1.1% L-lactic acid 0.1%
hydroxyethylcellulose
Water q.s. ad 100%
TABLE-US-00006 [0130] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 10.5 10.5 10.5 1/2 10.5 10.7 10.5 1 9.7 9.8 9.8 2 10.4 10.4
10.3 3 10.1 10.1 10.1 6 9.8 9.8 9.8
e) 2.6% active compound.about.2% free base 10% hydroxy propyl
betacyclodextrin
Water q.s. ad 100%
TABLE-US-00007 [0131] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 20.6 20.6 20.6 1/2 20.7 20.6 20.8 1 19.9 18.9 19.6 2 21.1
21.0 20.9 3 20.2 20.8 20.7 6 19.7 20.1
f. 2.6% active compound.about.2% free base 10% hydroxy propyl
betacyclodextrin 10% ethanol 96%
Water q.s. ad 100%
TABLE-US-00008 [0132] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 20.8 20.8 20.8 1/2 20.9 20.7 21.1 1 19.7 19.8 19.7 2 21.0
20.9 20.8 3 20.7 20.6 20.9 6 19.9 20.0
g) 2.6% active compound.about.2% free base 10% methyl
betacyclodextrin
Water q.s. ad 100%
TABLE-US-00009 [0133] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 20.8 20.8 20.8 1/2 19.6 19.3 19.6 1 21.0 20.4 20.6 2 20.0
20.5 20.2 3 20.8 21.1 21.0 6 20.3 19.9 19.6
h) 2.6% active compound.about.2% free base 10% methyl
betacyclodextrin 10% ethanol 96%
Water q.s. ad 100%
TABLE-US-00010 [0134] Time 25/60 40/75 60 (months:) mg/ml mg/ml
mg/ml 0 21.0 21.0 21.0 1/2 19.7 20.2 19.8 1 20.7 20.9 20.8 2 20.2
20.7 20.4 3 21.3 21.2 21.0 6 20.3 20.5 20.0
* * * * *